Hypersensitivity, Allergy, Autoimmunity, Immunodeficiency

Variable responses to antigen across a pop

weak → immunodeficiency (immunocomprimised)

too strong → hypersensitivity (type 1&4 = allergy)

Innate (primary) immune deficiency

CLAD → canine leukocyte adhesion deficiency

Primary (inherited) adaptive immune deficiencies

• 3 syndromes

• 4 breed predispositions

1. Equine SCID

   • autosomal recessive mutation

     • Defect DNA repair enzyme → required for VDJ recombination

   • no lymphocyte receptors

   • no functional B or T cells

   • agamma-globulin-aemic (no IgG) after MDA wanes (3 months

   • dies by 4-6 months → bronchopneumonia/sepsis

2. Canine X-linked SCID

   • affects Basset hounds & Corgis

   • affects 50% males

     dies by 4-6 months → bronchopneumonia/sepsis after MDA wanes (3 month)

     • due to IL-2R mutation

     • insertion mutation

     • causes premature stop codon

     • no extracellular binding domain

     • no cell proliferation (no clonal expansion)

3. Foal immunodeficiency Syndrome (Fell Pony)

   • B lymphocyte deficiency

   • no antibodies

   • profound + immunodeficiency

Breed specific [4]

• Young Weimaraners

  • constant infections

• Irish Wolfhounds

  • prone to rhinitis and bronchopneumonia

• Dachshunds and Cavalier King Charles Spaniels

  • penumocystitis (fungus) pneumononia - opportunistic

• Selective IgA deficiency of German Shepherd dogs + dysfunctional TLRs (type of PRR)

  • Defective PRRs → TOL5 + NOD2

  • compromised mucosal immunity → chronic diarrhoea

  • Crohnes (inflammatory bowel)

  • Anal furunculosis → necrotic ulcerations

  • Disseminated aspergillosus → fungal rhinitis beyond mucosa → systemic

Secondary immune deficiencies

1. Retrovirus induced immunosuppression

   • FeLV

   • FIV

2. Toxin induced immunosuppression

   • Bacteria and drugs (e.g. corticosteroids)

3. Malnutrition, stress (high cortisol), chronic disease, immunosenescence

   • General decline in naive T cells

Drugs causing immunosuppression

• Corticosteroids

• Ciclosporin

• Chemotherapy (cytotoxic) drugs

Suspecting underlying immunodeficiency

• Animal suffering from repeated infections that relapse following therapy

• Inherited → animals of prone breeds affected between 3-12 months

Immune tolerance

1. Negative selection (central tolerance)

2. Clonal anergy (peripheral tolerance)

3. Active Treg suppression

Immunological tolerance prevents overreaction → cytokine storm but enforces appropriate reaction

Prevents allergies

& autoimmune diseases

& hypersensitivities

1. Eliminating autoreactive T cells → clonal deletion

   • Some rescued to form natural Tregs

   • Positive selection → bind weakly to self antigens, strongly to nonself antigens → naive T cells

2. Clonal anergy

   • harmless antigen detected by TCR

   • No danger signal detected no PAMPs

   • OR antigen in immunopriviledged sites

3. Active suppression → Tregs

   • Thymus selection of natural Tregs

   • Induced Tregs develop in secondary lymphoid tissues

   • Make IL10 and TGF-Beta

Type 1 hypersensitivity

• Abnormal production of IgE to (environmental) antigen

• Mast cell sensitisation phase

• Re-exposure phase (2ndary reaction)

  • preferential eosinophil recruitment

Type 2 hypersensitivity

• Antigen-antibody complexes at fixed location

  • IgM/IgG

• IgG → neutralisation } myasthenia gravis (prevents Ach binding at NMJ)

• IgG → opsonisation:

  • Neonatal isoerythrolysis

  • Autoimmune haemolytic anaemia

  • Feline infectious anaemia (Mycoplasma haemofelis lives on RBC surface → immune response destroys RBCs)

  • Babesia → antigens bind to RBCs

Type 3 hypersensitivity → antibody (IgG) binds to SOLUBLE antigen

• Insoluble immune complexes in blood vessels → platelet aggregation → microthrombus formation → neutrophil recruitment and degranulation → complement activation → endothelium digestion → effusion

• Vasculitis →

  • Wet (effusive FIP) → biased TH2 response

  • Glomerulonephritis

  • Nonerosive immune mediate polyarthritis

  • Cutaneous drug reactions

    • Hypersensitivity to sulfonamide antibiotics → systemic vasculitis

Type 4 hypersensitivity

• T cell mediated → delayed

• Reaction 2-3 days later

Dry FIP → balanced TH1/TH2 response → granulomas

• If biased TH1 → virus would all be dead

Tuberculin test (TB)

• Inject purified avian/bovine TB protein derivative

• Measure skin thickness 72 hours later → if skin thicker then animal has had TB (re-exposed instead of sensitised)

1. Abnormal macrophage activation via CD4+ TH1 in healthy tissues

   • APCs present antigen to naive T → TH1

   • TH1 activates macrophages

   • Macrophage production of inflammatory mediators and matrix metalloproteinases (break down ECM)

2. Killer T cells destroying healthy cells

Type 1 hypersensitivity examples

• always allergic

1. FAD

2. CAD

3. Sweet itch (culicoides saliva)

4. Feline asthma

5. Canine allergic bronchitis

6. Equine inflammatory airway disease

7. Acute type 1 allergies

   • Urticaria

     • Dermal wheals, pruritus

   • Angioedema

     • Swelling of subcutaneous tissues → can obstruct respiration

   • Anaphylaxis

     • Systemic mast cell degranulation + histamine release

     • Decreases blood pressure → less blood to brain

     • Prodromal signs:

       • Dogs → hyperactive mast cells in gut → sudden onset vomiting + diarrhoea

       • Cats/humans → hyperactive mast cells in respiratory → dys-p-noea

Treatment of allergic skin disease

1. Allergen avoidance

2. Hypoallergenic diet

3. Topical shampoo

4. Immunotherapy (desensitisation)

5. Antihistamines

6. Prednisolone (synthetic cortisol)

7. Ciclosporin

8. Antibiotics (secondary infection)

Type 1 V type 4 hypersensitivities

Feature	Type I Hypersensitivity	Type IV Hypersensitivity
Also Known As	Immediate hypersensitivity	Delayed-type hypersensitivity
Onset Time	Minutes after exposure	24–72 hours after exposure
Key Immune Cells	Mast cells, basophils, eosinophils	T cells (especially Th1 and cytotoxic T cells)
Antibody Involvement	IgE	No antibodies involved
Mechanism	Allergen → IgE → Mast cell degranulation → histamine	Antigen → T cell activation → cytokine release MMPs and TNF-a
Examples	Asthma, anaphylaxis, hay fever	Contact dermatitis, tuberculin skin test, IBD-like responses
Treatment	Antihistamines, corticosteroids, epinephrine	Corticosteroids, immunosuppressants

Type 4 hypersensitivity examples

1. Rheumatoid arthritis

   • MMPs from synovial macrophages attack collagen in synovial fluid

   • MMPs also attack articular surface of joint (type 2 collagen)

   • MMPs digest joint surface, increasing bone-bone interaction → joint inflammation

2. Dry FIP

3. Hypothyroidism

   • Thyroglobulin autoantibodies → diagnostic marker (NOT CAUSE)

   • Caused by T cells killing thyroid

4. Dry eye (keratoconjunctivitis sicca)

   • Immune mediated destruction of lacrimal glands

   • Treat with ciclosporin eyedrops

2, 3, 4 are autoimmune, 1 is just hypersensitivity

Autoimmune type 2 hypersensitivity examples

1. Immune mediated haemolytic anaemia

   • Test via Coombs test

   • Antiglobulin antibodies (IgM/IgG detected)

   • Coombs positive → agglutination reaction

   • Coombs negative → pellet

   • Results in spherocytes → partially sphere shaped eaten RBCs

   • Haemolysis mediated by IgG:

     • opsonisation

     • complement activated

2. Thrombocytopenia

   • Haematuria, epistaxis, melaena (bloody faeces)

   • Petechial haemorrhages of skin and mucous membranes

   • Haematoma when withdrawing blood

   • Diagnosis:

     • Reduced platelet count

     • Antiplatelet antibodies

3. Pemphigus complex → vesiculo-bullous lesions

   • Antibodies bind to desmogleins of desmosomes → keratinocytes slough off from basement membrane

(these are the autoimmune ones - others were hypersensitivity only)

Type 3 hypersensitivity

• IgG binds to soluble antigens

Wet FIP

Systemic lupus erythe-mat-osus

• Production of antinuclear antibodies (target DNA or histones) → targets all nucleated cells

Polyarthritis

IMHA or IMTP (if causing vasculitis)

Glomerulonephritis

• Type III hypersensitivity reaction when immune complexes deposit in glomeruli, triggering inflammation and damage

Systematic lupus erythematosus diagnosis

Antinuclear antibody test

• Grow nucleated cells on microscope slide

• Add serum from patient → allows antibodies to bind

• Antibodies bind to fluorescence conjugate → uses immunofluorescence

  • [can also make glomerulonephritis immune complexes fluoresce]

Treatment of autoimmune diseases

1. Prednisolone

2. Ciclosporine

3. Aza-thio-prine = cytotoxic chemotherapy drug → immunosuppression

4. Anti-TNF anti-body therapy

   • monoclonal antibodies for rheumatoid arthritis

Autoimmune susceptibility factors

Genetic

• MHC genes

• Dysfunctional genes

  • HLA-DR3/DR4

• Immune response genes

  • TNF-a

  • CTLA4

Hormonal

• Progesterone and oestrogen increase lupus susceptibility

• Testosterone protective

Environmental

• High stress

• Bad diet

• Insufficient vit D